Evidence from clinical observations and experimental results, previously reported, suggest the presence of an insulin resistance, particularly in the skeletal muscle of severely injured infected patients. The resulting fuel deficit in muscle leads to oxidation of certain amino acids and a release of alanine and other glucogenic precursors. This concept explains not only the proteolysis and ultimate reduction of protein synthesis, but also the elevated glucose turnover rate and glucose pool observed in such patients. Circulating agents (probably peptides) have been found in the plasma of septic patients which induce these metabolic responses in animal muscle both in vivo and in vitro. Based upon this hypothesis experiments will continue employing bioassays, immunoassays, and isolation techniques to demonstrate in greater detail the nature and mode of action of these active substances in the blood plasma of septic or injured patients.